Project Summary: Histone deacetylases (HDACs) have emerged as an important mechanism in regulating cardiovascular diseases, and this holds promise in developing efficacious and clinical relevant therapeutic strategies. This is a competitive renewal application to continue our studies of HDAC inhibition, which is critical to the development of myocardial protection. During the past funding periods, we have well established that inhibition of HDAC leads to a profound cardioprotection in attenuating myocardial I/R injury and reversing cardiac remodeling. We have discovered that p38 is subject to regulation by acetylation, and p38 acetylation is associated with HDAC inhibition-induced cardioprotective effects. We have demonstrated that HDAC inhibition enhances cardiac repair through stimulating endogenous myoangiogenesis. Non-specific HDAC inhibition is conceived as a major hurdle to achieving a promising therapeutic implication in the future. Our recent studies have sought to explore the significance of HDAC isoforms in modulating cardiac pathophysiology. Our interesting observation indicated that HDAC 4 isoform mainly involves HDAC inhibitors-induced cellular protection, which was associated with the degradation of HDAC4 protein. p38-regulated/activated kinase (PRAK), an identified novel and poorly characterized p38 substrate, is crucial to enhancing angiogenesis. Our latest discovery indicates that genetic inhibition of PRAK eliminated HDAC inhibition-induced cardioprotection and mitigated angiogenesis. These findings have led us to speculate that inhibition of HDAC4 and subsequent PRAK activation occurs following HDAC inhibition, leading to protective effects. The proposed studies will test the central hypothesis that HDAC4 inhibition-mediated PRAK activation induces myocardial protection and angiogenesis. The specific aims of our proposed studies are the following: Specific Aim 1: Determine the role of HDAC4 and its ubiquitination in mediating myocyte survival in hypoxia in vitro. Specific Aim 2: Determine the in vivo role of cardiac-specific HDAC4 and HDAC inhibitor in myocardial ischemia and angiogenesis. Specific Aim 3: Elucidate HDAC4 deletion or HDAC inhibitor-mediated protection and angiogenesis via PRAK signaling. Specific Aim 4: Define preclinical perspectives of HDAC inhibitor-mediated protection is proteasome pathway using a preclinical large animal model. Taken together, the proposed studies of this competitive renewal application will for the first time establish that HDAC4 associated with PRAK constitutes a crucial pathway to mediate myocardial injury and angiogenesis. All of these studies will not only uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will provide the translational evidence that will have great potential to develop a new therapeutic approach to improve human health.